Immune checkpoint therapy-elicited sialylation of IgG antibodies impairs antitumorigenic type I interferon responses in hepatocellular carcinoma
Immune checkpoint therapy-elicited sialylation of IgG antibodies impairs antitumorigenic type I interferon responses in hepatocellular carcinoma
复制标题
免疫检查点治疗引起的 IgG 抗体唾液酸化会损害肝细胞癌中的抗肿瘤 I 型干扰素反应
DOI：
10.1016/j.immuni.2022.11.014
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发表时间：
2023-01-10
期刊：
影响因子：
32.4
通讯作者：
Kuang，Dong-Ming
中科院分区：
文献类型：
--
作者：
Wu，Rui-Qi;Lao，Xiang-Ming;Kuang，Dong-Ming
抗肿瘤T细胞对免疫检查点阻断（ICB）治疗的反应是很好的。然而，ICB治疗是否以及如何在癌症环境中操纵抗体介导的免疫反应仍然是难以捉摸的。利用串联质谱法分析肝癌组织免疫球蛋白G （IgG）的修饰，我们确定了ICB治疗在催化Fc区IgG唾液化中的作用。效应T细胞通过干扰素(IFN)-γ- st6gal - i依赖途径触发IgG唾液化。DC-SIGN+巨噬细胞是唾液化IgG的主要靶细胞。DC-SIGN与唾液化的IgG相互作用后，刺激raf -1诱导ATF3升高，使cGAS-STING通路失活，并消除随后i型ifn触发的抗肿瘤免疫。虽然肿瘤中IgG唾液化的增强预示着接受ICB治疗的患者的治疗效果改善，但阻碍IgG唾液化增强了ICB治疗后的抗肿瘤T细胞免疫。因此，靶向抗体负反馈作用的ICB治疗具有提高肿瘤免疫治疗疗效的潜力。
The reinvigoration of anti-tumor T cells in response to immune checkpoint blockade (ICB) therapy is well established. Whether and how ICB therapy manipulates antibody-mediated immune response in cancer environments, however, remains elusive. Using tandem mass spectrometric analysis of modification of immunoglobulin G (IgG) from hepatoma tissues, we identified a role of ICB therapy in catalyzing IgG sialylation in the Fc region. Effector T cells triggered sialylation of IgG via an interferon (IFN)-γ-ST6Gal-I-dependent pathway. DC-SIGN+macrophages represented the main target cells of sialylated IgG. Upon interacting with sialylated IgG, DC-SIGN stimulated Raf-1-elicited elevation of ATF3, which inactivated cGAS-STING pathway and eliminated subsequent type-I-IFN-triggered antitumorigenic immunity. Although enhanced IgG sialylation in tumors predicted improved therapeutic outcomes for patients receiving ICB therapy, impeding IgG sialylation augmented antitumorigenic T cell immunity after ICB therapy. Thus, targeting antibody-based negative feedback action of ICB therapy has potential for improving efficacy of cancer immunotherapies.